Methods for Reducing Noise in Optical Biological Sensors

ABSTRACT

Optical measurement of physiological parameters with wearable devices often includes measuring signals in the presence of significant noise sources. These noise sources include, but are not limited to, noise associated with: variable optical coupling to skin or tissue, variations in tissue optical properties with time due to changes in humidity, temperature, hydration, variations in tissue optical properties between individuals, variable coupling of ambient light sources into detectors, and instrument and detector noise, including electrical noise, radio frequency or magnetic interference, or noise caused by mechanical movement of the detector or its components. The present disclosure includes devices and methods configured to produce representations of the raw data in which noise, broadly defined, is separated from the data of interest. The disclosed devices and methods may include subtracting or calibrating out these noise sources and other spurious fluctuations in wearable devices with optical sensors.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional patent application claimingpriority to U.S. application Ser. No. 14/319,182 filed Jun. 30, 2014,the contents of which are hereby incorporated by reference.

BACKGROUND

Unless otherwise indicated herein, the materials described in thissection are not prior art to the claims in this application and are notadmitted to be prior art by inclusion in this section.

A number of scientific methods have been developed in the medical fieldto evaluate physiological conditions of a person by detecting and/ormeasuring one or more analytes in a person's blood or other bodilyfluids or tissues. The one or more analytes could be any analytes that,when present in or absent from the blood, or present at a particularconcentration or range of concentrations, may be indicative of a medicalcondition or health state of the person. The one or more analytes couldinclude enzymes, reagents, hormones, proteins, cells or other molecules,such as carbohydrates, e.g., glucose.

In a typical scenario, a person's blood is drawn and either sent to alab or input into a handheld testing device, such as a glucose meter,where one or more tests are performed to measure various analyte levelsand parameters in the blood. For most people, the blood tests areinfrequent, and an abnormal analyte level indicative of a medicalcondition may not be identified until the next blood test is performed.Even in the case of relatively frequent blood testing, such as may befound with those with diabetes, who regularly draw blood to test forblood glucose concentration, those blood tests are typically performedwhen the user is awake, although the blood glucose levels (and potentialvariations in such levels) occurring during the night could provideimportant information to assist a physician in assessing that person'smedical condition. Further, most known methods of analyte detection andanalysis require the collection of blood or other bodily fluid samples,which may be inconvenient, invasive and require significant patientcompliance.

Moreover, some blood analytes are particularly difficult to identify andquantify with conventional sensing techniques. For small or rarifiedanalytes, such as circulating tumor cells, for example, only 1 such cellmay be present in 10 mL of blood. Impractically large quantities ofblood would have to be drawn or otherwise sampled and analyzed in orderto catch such cells with statistical significance.

Methods for analyte detection and characterization often suffer from alow signal-to-noise ratio (SNR), since the signal obtained from theanalyte (in general, a small object) is typically weak in comparison tothe background. This can make discerning between target analytes presentin the blood, versus other analytes, particles, and tissues, etc.present in the blood and elsewhere in the body can be very difficult,especially where the measurements are taken non-invasively from outsidethe body. This is particularly true with some methods of analytecharacterization, such as optical methods, or where the target analytesare rare in the blood or are of a relatively small size. Accordingly,such measurements can be much more time consuming (if a large volume ofblood must be analyzed), less sensitive, less specific and generallyless informative on the whole. For example, with fluorescence detectiontechniques, it is often difficult to obtain highly sensitivemeasurements of a target analyte because other tissues, cells, andmolecules in the body may have some inherent fluorescent properties,creating a high level of background noise.

SUMMARY

In a first aspect, a method is provided. The method includes providing,in a wearable medical diagnostic device, a first and a second opticalsignal transmitted from within a lumen of subsurface vasculature. Thefirst optical signal includes an unfiltered target signal and a firstnoise signal. The second optical signal includes a second noise signal.The first and second noise signals are correlated and a quotient of theunfiltered target signal and the first noise signal includes anunfiltered signal to noise ratio. The method further includesdetermining a filtered signal, based at least on the unfiltered targetsignal, the first noise signal, and the second noise signal. Thefiltered signal includes a filtered target signal and a filtered noisesignal. A quotient of the filtered target signal and the filtered noisesignal includes a filtered signal to noise ratio in which the filteredsignal to noise ratio is higher than the unfiltered signal to noiseratio.

In a second aspect, a wearable medical diagnostic device is provided.The wearable medical diagnostic device includes at least one detectorand a computing device. The at least one detector is configured toprovide an unfiltered target signal, a first noise signal, and a secondnoise signal. The unfiltered target signal is transmitted substantiallyfrom within a lumen of subsurface vasculature. The first and secondnoise signals are correlated and a quotient of the unfiltered targetsignal and the first noise signal includes an unfiltered signal to noiseratio. The computing device is configured to determine a filteredsignal, based at least on the unfiltered target signal, the first noisesignal, and the second noise signal. The filtered signal includes afiltered target signal and a filtered noise signal. A quotient of thefiltered target signal and the filtered noise signal includes a filteredto noise ratio in which the filtered signal to noise ratio is higherthan the unfiltered signal to noise ratio.

In a third aspect, a non-transitory computer readable medium isprovided. The non-transitory computer readable medium includesinstructions executable by a computing device to cause the computingdevice to perform functions, the functions including receiving, in awearable medical diagnostic device, a first and a second optical signaltransmitted from within a lumen of subsurface vasculature. The firstoptical signal includes an unfiltered target signal and a first noisesignal. The second optical signal includes a second noise signal. Thefirst and second noise signals are correlated. The quotient of theunfiltered target signal and the first noise signal includes anunfiltered signal to noise ratio. The functions further includedetermining a filtered signal, based at least on the unfiltered targetsignal, the first noise signal, and the second noise signal. Thefiltered signal includes a filtered target signal and a filtered noisesignal. A quotient of the filtered target signal and the filtered noisesignal includes a filtered signal to noise ratio in which the filteredsignal to noise ratio is higher than the unfiltered signal to noiseratio.

These as well as other aspects, advantages, and alternatives, willbecome apparent to those of ordinary skill in the art by reading thefollowing detailed description, with reference where appropriate to theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an example wearable device, according toan illustrative embodiment.

FIG. 2A is a perspective top view of an example wrist-mounted device,when mounted on a wearer's wrist, according to an illustrativeembodiment.

FIG. 2B is a perspective bottom view of an example wrist-mounted deviceshown in FIG. 2A, when mounted on a wearer's wrist, according to anillustrative embodiment.

FIG. 3A is a perspective bottom view of an example wrist-mounted device,when mounted on a wearer's wrist, according to an illustrativeembodiment.

FIG. 3B is a perspective top view of an example wrist-mounted deviceshown in FIG. 3A, when mounted on a wearer's wrist, according to anillustrative embodiment.

FIG. 3C is a perspective view of an example wrist-mounted device shownin FIGS. 3A and 3B, according to an illustrative embodiment.

FIG. 4A is a perspective view of an example wrist-mounted device,according to an illustrative embodiment.

FIG. 4B is a perspective bottom view of an example wrist-mounted deviceshown in FIG. 4A, according to an illustrative embodiment.

FIG. 5 is a perspective view of an example wrist-mounted device,according to an illustrative embodiment.

FIG. 6 is a perspective view of an example wrist-mounted device,according to an illustrative embodiment.

FIG. 7 is a block diagram of an example system that includes a pluralityof wearable devices in communication with a server, according to anillustrative embodiment.

FIG. 8 is a functional block diagram of an example wearable device,according to an illustrative embodiment.

FIG. 9 is a functional block diagram of an example wearable device,according to an illustrative embodiment.

FIG. 10 is a flowchart of an example method for operating a wearabledevice, according to an illustrative embodiment.

FIG. 11A is a side partial cross-sectional view of a wrist-mounteddevice, while on a human wrist, according to an illustrative embodiment.

FIG. 11B is a side partial cross-sectional view of a wrist-mounteddevice, while on a human wrist, according to an illustrative embodiment.

FIG. 12A is a side partial cross-sectional view of a wrist-mounteddevice, while on a human wrist, according to an illustrative embodiment.

FIG. 12B is a side partial cross-sectional view of a wrist-mounteddevice, while on a human wrist, according to an illustrative embodiment.

FIG. 13A is a side partial cross-sectional view of a wrist-mounteddevice, while on a human wrist, according to an illustrative embodiment.

FIG. 13B is a side partial cross-sectional view of a wrist-mounteddevice, while on a human wrist, according to an illustrative embodiment.

FIG. 14 is a functional block diagram of a wearable medical diagnosticsystem with noise reduction, according to an illustrative embodiment.

FIG. 15 is a functional block diagram of a wearable medical diagnosticsystem with noise reduction, according to an illustrative embodiment.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying figures, which form a part hereof. In the figures, similarsymbols typically identify similar components, unless context dictatesotherwise. The illustrative embodiments described in the detaileddescription, figures, and claims are not meant to be limiting. Otherembodiments may be utilized, and other changes may be made, withoutdeparting from the scope of the subject matter presented herein. It willbe readily understood that the aspects of the present disclosure, asgenerally described herein, and illustrated in the figures, can bearranged, substituted, combined, separated, and designed in a widevariety of different configurations, all of which are explicitlycontemplated herein.

Further, while embodiments disclosed herein make reference to use on orin conjunction with a living human body, it is contemplated that thedisclosed methods, systems and devices may be used in any environmentwhere non-invasive detection of an analyte is desired. The environmentmay be any living or non-living body or a portion thereof, a fluidconduit, a fluid reservoir, etc. For example, one of skill in the artwill recognize that the embodiments disclosed herein may be used tosense analytes present in a water system. Moreover, while the presentdisclosure describes embodiments for use in vivo, one of skill in theart will also recognize that in vitro applications are possible as well.Accordingly, the environment may also include a test tube or othervessel for holding a fluid.

I. OVERVIEW

A diagnostic system can non-invasively detect and measure a plurality ofphysiological parameters of a person, which can include any parametersthat may relate to the person's health. For example, the system couldinclude sensors for measuring blood pressure, pulse rate, skintemperature, etc. At least some of the physiological parameters may beobtained by the system non-invasively detecting and/or measuring one ormore analytes in blood circulating in subsurface vasculature. The one ormore analytes could be any analytes that, when present in or absent fromthe blood, or present at a particular concentration or range ofconcentrations, may be indicative of a medical condition or health ofthe person. For example, the one or more analytes could include enzymes,hormones, proteins, cells, or other molecules.

In an example embodiment, the system obtains at least some of thehealth-related information by detecting the binding or interaction of aclinically-relevant analyte to or with particles, for example,microparticles or nanoparticles, introduced into a lumen of thesubsurface vasculature that have been functionalized with a receptorthat has a specific affinity to bind to or interact with the specificanalyte. The term “binding” is understood in its broadest sense to alsoinclude a detectable interaction between the clinically-relevant analyteand the functionalized particles. The functionalized particles can beintroduced into the person's blood stream by injection, ingestion,inhalation, transdermally, or in some other manner.

The particles can be functionalized by covalently or otherwise attachingor associating a receptor that specifically binds or otherwise interactswith a particular clinically-relevant analyte. The functionalizedreceptor may be an antibody, peptide, nucleic acid, phage, bacteria,virus, aptamer or any other molecule with a defined affinity for atarget analyte. Additionally or alternatively, the receptor may beinherent to the particle itself. For example, the particle itself may bea virus or a phage with an inherent affinity for certain analytes. Othercompounds or molecules, such as fluorophores or autofluorescent orluminescent markers or non-optical contrast agents (e.g. acousticimpedance contrast, RF contrast and the like), which may assist ininterrogating the particles in vivo, may also be attached to theparticles.

The particles can have a diameter that is less than about 20micrometers. In some embodiments, the particles have a diameter on theorder of about 10 nanometers to 1 micrometer. In further embodiments,small particles on the order of 10-100 nanometers in diameter may beassembled to form a larger “clusters” or “assemblies on the order of1-10 micrometers. Those of skill in the art will understand a “particle”in its broadest sense and that it may take the form of any fabricatedmaterial, a molecule, cryptophan, a virus, a phage, etc. Further, aparticle may be of any shape, for example, spheres, rods,non-symmetrical shapes, etc.

In some examples, the particles may also be magnetic and can be formedfrom a paramagnetic, super-paramagnetic or ferromagnetic material or anyother material that responds to a magnetic field. Alternatively, theparticles may also be made of non-magnetic materials such aspolystyrene. Where magnetic particles are used, the system may include amagnet that can direct into the portion of subsurface vasculature amagnetic field that is sufficient to manipulate functionalized magneticparticles in a lumen of that portion of subsurface vasculature, forexample, to collect or slow down in a certain area. However,measurements may be taken without localized “collection” of thefunctionalized particles. The system may be configured to activate themagnetic field periodically, such as at certain times of the day (e.g.,every hour).

The system may further include one or more data collection systems forinterrogating, in a non-invasive manner, a target analyte present in alumen of the subsurface vasculature in a particular local area. Forexample, the system may include a detector configured to detect aresponse signal transmitted from a portion of subsurface vasculature.The response signal may include both an analyte response signal and abackground noise signal.

In an example embodiment, the analyte response signal could includelight emitted from the target analyte. For example, the target analytemay include a chemiluminescent marker, such as a fluorophore, configuredto produce a response signal in the form of light. The analyte responsesignal may include light emitted in response to a chemical reactionand/or biological interaction.

In some examples, the system may also include an interrogating signalsource for transmitting an interrogating signal that can penetrate intoa portion of subsurface vasculature, or another body system, and adetector for detecting a response signal that is transmitted from theportion of subsurface vasculature, or other body system, in response tothe interrogating signal. The interrogating signal may be any kind ofsignal that is benign to the patient, and may such as electromagnetic,magnetic, optic, acoustic, thermal, mechanical, or electric. Aninteraction, for example between the interrogating signal and theportion of subsurface vasculature, may result in a response signal thatmay be used to measure a physiological parameter or, more particularly,that may detect and/or measure the presence of the clinically-relevantanalyte and/or the binding or interaction between the analyte and otherchemical or biological elements.

In an illustrative embodiment, the analyte response may be related to aninteraction between one or more target analytes and the interrogatingsignal source. For example, the interrogating signal source couldinclude a light emitting diode or laser. The interrogating signal sourcemay be configured to emit within narrow or wide bands throughout theelectromagnetic spectrum. The target analyte may include a fluorophore.The fluorophore may be configured to emit light in response toexcitation from the interrogating signal source. The light emitted fromthe fluorophore may represent the analyte response signal. The analyteresponse signal may occur anywhere in the electromagnetic spectrum.

For example, the interrogating signal may include a radio frequency (RF)signal and the response signal is a magnetic resonance signal, such asnuclear magnetic resonance (NMR). In another example, where thefunctionalized particles include a fluorophore, the interrogating signalmay be an optical signal with a wavelength that can excite thefluorophore and penetrate the skin or other tissue and subsurfacevasculature (e.g., a wavelength in the range of about 500 to about 1000nanometers). The response signal may include fluorescence radiation fromthe fluorophore that can penetrate the subsurface vasculature and tissueto reach the detector. In another example, where the functionalizedparticles include an electrically conductive material or a magneticallylossy material, the interrogation signal may be a time-varying magneticfield or a radio frequency (RF) electromagnetic signal, with sufficientsignal power to rapidly heat the particles. The response signal may bean acoustic emission from the particles, caused by rapid thermalexpansion of the particles, or caused by cavitation of the liquid mediumin contact with the particles.

Additionally, the system may further include a modulation sourceconfigured to modulate the analyte response signal. The modulationsource can be configured to modulate the analyte response signaldifferently than the background noise signal. To this end, themodulation may help to discern between the target analyte and,essentially, everything else in the body by, for example, increasing thesignal-to-noise ratio. Generally, the modulation may include anyspatial, temporal, spectral, thermal, magnetic, mechanical, electrical,acoustic, chemical, or electrochemical, etc. modulation technique or anycombination thereof.

In some scenarios, it may also be useful to detect and distinguish boththe analyte response signal—related to functionalized particles bound toor interacting with target analyte(s)—and an “unbound” particlesignal—related to functionalized particles not bound to or interactingwith target analyte(s). For example, in some measurement orcharacterization schemes, it may be useful or necessary to determine thepercentage of functionalized particles introduced into the body thathave bound to the target analyte. In such cases, the modulation sourcemay be configured to modulate the analyte response signal differentlythan the unbound particle signal.

The elements of the system, namely the type of modulation, thetype/shape/materials of particles, types of receptors and targetanalytes may all be interrelated. Ultimately, the type of particle andreceptor used to detect a particular target analyte may be dictated, tosome extent, by the characteristics of the target analyte (i.e., type,size, shape, affinities, etc.), the chosen type of modulation (i.e.,spatial, spectral, thermal, magnetic, mechanical, chemical, etc.), andthe mode of interrogation (optical, acoustic, magnetic, RF, etc.).

Data collected by the detector may be sent to a processor for analysis.The processor may be configured to non-invasively detect the one or moretarget analytes by differentiating the analyte response signal from thebackground noise signal based, at least in part, on the modulation. Insome cases where the analyte includes a bound particle, the processormay further be configured to differentiate the analyte response signalfrom the unbound particle signal.

The processor may be configured to determine the concentration of aparticular target analyte in the blood from, at least in part, theanalyte response signal. The detection and concentration data processedby the processor may be communicated to the patient, transmitted tomedical or clinical personnel, locally stored or transmitted to a remoteserver, the cloud, and/or any other system where the data may be storedor accessed at a later time.

The processor may be located on an external reader, which may beprovided as an external body-mounted device, such as a necklace,wristwatch, eyeglasses, a mobile phone, a handheld or personal computingdevice or some combination thereof. Data collected by the detector maybe transmitted to the external reader via a communication interface.Control electronics can wirelessly communicate the data to the externalreader by modifying the impedance of an antenna in communication withthe detector so as to characteristically modify the backscatter from theantenna. In some examples, the external reader can operate tointermittently interrogate the detector to provide a reading byradiating sufficient radiation to power the detector to obtain ameasurement and communicate the result. In this way, the external readercan acquire a series of analyte identification and concentrationmeasurements over time without continuously powering the detector and/orprocessor. The processor may also be provided at another location distalto the detector, and the detector data is communicated to the processorvia a wired connection, a memory card, a USB device or other knownmethod. Alternatively, the processor may be located proximal to thedetector and may be configured to locally analyze the data that itcollects and then transmit the results of the analysis to an externalreader or server.

The external reader may include a user interface, or may furthertransmit the collected data to a device with a user interface that canindicate the results of the data analysis. In this way, the personwearing, holding or viewing the device can be made aware of thenutritional analysis and/or potential medical conditions. The externalreader may also be configured to produce an auditory or tactile(vibration) response to alert the patient of a medical condition.Further, the external reader may also be configured to receiveinformation from the patient regarding his/her health state, wellnessstate, activity state, nutrition intake and the like, as additionalinput information to the processor. For example, the user may input ahealth or wellness state, such as, experiencing migraine symptoms,jittery, racing heart, upset stomach, feeling tired, activity stateincluding types and duration of physical activity nutrition intakeincluding meal timing and composition, and other parameters includingbody weight, medication intake, quality of sleep, stress level, personalcare products used, environmental conditions, social activity, etc.Further, the reader may also receive signals from one or more otherdetectors, such as a pedometer, heart rate sensor, blood pressuresensor, blood oxygen saturation level, body temperature, GPS or otherlocation or positioning sensors, microphone, light sensor, etc.

The system may be configured to obtain data during pre-set measurementperiods or in response to a prompt. For example, the system may beconfigured to operate the detector and collect data once an hour. Inother examples, the system may be configured to operate the detector inresponse to a prompt, such as a manual input by the patient or aphysician. The system may also be configured to obtain data in responseto an internal or external event or combination of events, such asduring or after physical activity, at rest, at high pulse rates, high orlow blood pressures, cold or hot weather conditions, etc. In otherexamples, the system could operate the detector more frequently or lessfrequently, or the system could measure some analytes more frequentlythan others.

Data collected by the system may be used to notify the patient of, asdescribed above, analyte levels or of an existing or imminent medicalemergency. In some examples, the data may be used to develop anindividual baseline profile for the patient. The baseline profile mayinclude patterns for how one or more of the patient's analyte levelstypically change over time, such as during the course of a day, a week,or a month, or in response to consumption of a particular type offood/drug. The baseline profile, in essence, may establish “normal”levels of the measured analytes for the patient. Additional data,collected over additional measurement periods, may be compared to thebaseline profile. If the additional data is consistent with the patternsembodied in the baseline profile, it may be determined that thepatient's condition has not changed. On the other hand, if theadditional data deviates from the patterns embodied in the baselineprofile, it may be determined that the patient's condition has changed.The change in condition could, for example, indicate that the patienthas developed a disease, disorder, or other adverse medical condition ormay be at risk for a severe medical condition in the near future.Further, the change in condition could further indicate a change in thepatient's eating habits, either positively or negatively, which could beof interest to medical personnel. Further, the patient's baseline anddeviations from the baseline can be compared to baseline and deviationdata collected from a population of wearers of the devices.

When a change in condition is detected, a clinical protocol may beconsulted to generate one or more recommendations that are appropriatefor the patient's change in condition. For example, it may berecommended that the patient inject himself/herself with insulin, changehis/her diet, take a particular medication or supplement, schedule anappointment with a medical professional, get a specific medical test, goto the hospital to seek immediate medical attention, abstain fromcertain activities, etc. The clinical protocol may be developed based,at least in part, on correlations between analyte concentration andhealth state derived by the server, any known health information ormedical history of the patient, and/or on recognized standards of carein the medical field. The one or more recommendations may then betransmitted to the external reader for communication to the user via theuser interface.

Correlations may be derived between the analyte concentration(s)measured by the system and the health state reported by the patient. Forexample, analysis of the analyte data and the health state data mayreveal that the patient has experienced certain adverse healthconditions, such as a migraine or a heart attack, when an analytereaches a certain concentration. This correlation data may be used togenerate recommendations for the patient, or to develop a clinicalprotocol. Blood analysis may be complemented with other physiologicalmeasurements such as blood pressure, heart rate, body temperature etc.,in order to add to or enhance these correlations.

Further, data collected from a plurality of patients, including both theanalyte measurements and the indications of health state, may be used todevelop one or more clinical protocols used by the server to generaterecommendations and/or used by medical professionals to provide medicalcare and advice to their patients. This data may further be used torecognize correlations between blood analytes and health conditionsamong the population. Health professionals may further use this data todiagnose and prevent illness and disease, prevent serious clinicalevents in the population, and to update clinical protocols, courses oftreatment, and the standard of care.

The above described system may be implemented as a wearable device. Theterm “wearable device,” as used in this disclosure, refers to any devicethat is capable of being worn at, on or in proximity to a body surface,such as a wrist, ankle, waist, chest, ear, eye or other body part. Inorder to take in vivo measurements in a non-invasive manner from outsideof the body, the wearable device may be positioned on a portion of thebody where subsurface vasculature is easily observable, thequalification of which will depend on the type of detection system used.The device may be placed in close proximity to the skin or tissue, butneed not be touching or in intimate contact therewith. A mount, such asa belt, wristband, ankle band, headband, etc. can be provided to mountthe device at, on or in proximity to the body surface. The mount mayprevent the wearable device from moving relative to the body to reducemeasurement error and noise. Further, the mount may be an adhesivesubstrate for adhering the wearable device to the body of a wearer. Thedetector, modulation source, interrogation signal source (if applicable)and, in some examples, the processor, may be provided on the wearabledevice. In other embodiments, the above described system may beimplemented as a stationary measurement device to which a user must bebrought into contact or proximity with or as a device that may betemporarily placed or held against a body surface during one or moremeasurement periods.

In an illustrative embodiment, the processor and/or other elements ofthe system may be configured in an effort to optimize signal to noiseratio. For example, the system may be configured to compare two or moresignal channels whose noise is correlated. One of the signal channelsmay substantially contain the signal of interest, while each of thesignal channels may contain well-correlated noise signals. Throughsubtraction, division, and/or other signal processing algorithms, asignal of interest may be separated from the noise signals, which mayresult in a higher signal to noise ratio.

It should be understood that the above embodiments, and otherembodiments described herein, are provided for explanatory purposes, andare not intended to be limiting.

Further, the term “medical condition” as used herein should beunderstood broadly to include any disease, illness, disorder, injury,condition or impairment—e.g., physiologic, psychological, cardiac,vascular, orthopedic, visual, speech, or hearing—or any situationrequiring medical attention.

II. ILLUSTRATIVE WEARABLE DEVICES

A wearable device 100 may automatically measure a plurality ofphysiological parameters of a person wearing the device. The term“wearable device,” as used in this disclosure, refers to any device thatis capable of being worn at, on or in proximity to a body surface, suchas a wrist, ankle, waist, chest, or other body part. In order to take invivo measurements in a non-invasive manner from outside of the body, thewearable device may be positioned on a portion of the body wheresubsurface vasculature is easily observable, the qualification of whichwill depend on the type of detection system used. The device may beplaced in close proximity to the skin or tissue, but need not betouching or in intimate contact therewith. A mount 110, such as a belt,wristband, ankle band, etc. may be provided to mount the device at, onor in proximity to the body surface. The mount 110 may prevent thewearable device from moving relative to the body to reduce measurementerror and noise. In one example, shown in FIG. 1, the mount 110, maytake the form of a strap or band 120 that can be worn around a part ofthe body. Further, the mount 110 may be an adhesive substrate foradhering the wearable device 100 to the body of a wearer.

A measurement platform 130 is disposed on the mount 110 such that it canbe positioned on the body where subsurface vasculature is easilyobservable. An inner face 140 of the measurement platform is intended tobe mounted facing to the body surface. The measurement platform 130 mayhouse the data collection system 150, which may include at least onedetector 160 for detecting at least one physiological parameter, whichmay include one or more parameters that may relate to the health of theperson wearing the wearable device. For example, the detector 160 couldbe configured to measure blood pressure, pulse rate, respiration rate,skin temperature, etc. At least one of the detectors 160 may beconfigured to non-invasively measure one or more analytes in bloodcirculating in subsurface vasculature proximate to the wearable device.In a non-exhaustive list, detector 160 may include any one of an optical(e.g., CMOS, CCD, photodiode), acoustic (e.g., piezoelectric,piezoceramic), electrochemical (voltage, impedance), thermal, mechanical(e.g., pressure, strain), magnetic, or electromagnetic (e.g., magneticresonance) sensor. The components of the data collection system 150 maybe miniaturized so that the wearable device may be worn on the bodywithout significantly interfering with the wearer's usual activities.

In some examples, the data collection system 150 further includes asignal source 170 for transmitting an interrogating signal through thesurface of the wearer's skin into the portion of subsurface vasculature,for example, into a lumen of the subsurface vasculature. Theinterrogating signal may be any kind of signal that is benign to thewearer, such as electromagnetic, magnetic, optic, acoustic, thermal,mechanical, and results in a response signal that can be used to measurea physiological parameter or, more particularly, that can detect thebinding of the clinically-relevant analyte to the functionalizedparticles. In one example, the interrogating signal is anelectromagnetic pulse (e.g., a radio frequency (RF) pulse) and theresponse signal is a magnetic resonance signal, such as nuclear magneticresonance (NMR). In another example, the interrogating signal is atime-varying magnetic field, and the response signal is anexternally-detectable physical motion due to the time-varying magneticfield. The time-varying magnetic field modulates the particles byphysical motion in a manner different from the background, making themeasier to detect. In a further example, the interrogating signal is anelectromagnetic radiation signal. In particular, the interrogatingsignal may be electromagnetic radiation having a wavelength betweenabout 400 nanometers and about 1600 nanometers. The interrogating signalmay, more particularly, comprise electromagnetic radiation having awavelength between about 500 nanometers and about 1000 nanometers. Insome examples, the functionalized particles include a fluorophore. Theinterrogating signal may therefore be an electromagnetic radiationsignal with a wavelength that can excite the fluorophore and penetratethe skin or other tissue and subsurface vasculature (e.g., a wavelengthin the range of about 500 to about 1000 nanometers), and the responsesignal is fluorescence radiation from the fluorophore that can penetratethe subsurface vasculature and tissue to reach the detector.Alternatively, the interrogating signal may include electromagneticradiation with wavelengths outside the 400-1600 nm range.

In some cases, an interrogating signal is not necessary to measure oneor more of the physiological parameters and, therefore, the wearabledevice 100 need not include a signal source 170. For example, thefunctionalized particles may include an autofluorescent or luminescentmarker, such as a fluorophore, that will automatically emit a responsesignal indicative of the binding of the clinically-relevant analyte tothe functionalized particles, without the need for an interrogatingsignal or other external stimulus. In some examples, the functionalizedparticles may include a chemiluminescent marker configured to produce aresponse signal in the form of luminescence radiation produced inresponse to a chemical reaction initiated, at least in part, to thebinding of the target analyte to the particle.

A collection magnet 180 may also be included in the data collectionsystem 150. In such embodiments, the functionalized particles may alsobe made of or be functionalized with magnetic materials, such asferromagnetic, paramagnetic, super-paramagnetic, or any other materialthat responds to a magnetic field. The collection magnet 180 may beconfigured to direct a magnetic field into the portion of subsurfacevasculature that is sufficient to cause functionalized magneticparticles to collect in a lumen of that portion of subsurfacevasculature. The magnet may be an electromagnet that may be turned onduring measurement periods and turned off when a measurement period iscomplete so as to allow the magnetic particles to disperse through thevasculature.

The wearable device 100 may also include a user interface 190 via whichthe wearer of the device may receive one or more recommendations oralerts generated either from a remote server or other remote computingdevice, or from a processor within the device. The alerts could be anyindication that can be noticed by the person wearing the wearabledevice. For example, the alert could include a visual component (e.g.,textual or graphical information on a display), an auditory component(e.g., an alarm sound), and/or tactile component (e.g., a vibration).Further, the user interface 190 may include a display 192 where a visualindication of the alert or recommendation may be displayed. The display192 may further be configured to provide an indication of the measuredphysiological parameters, for instance, the concentrations of certainblood analytes being measured.

In one example, the wearable device is provided as a wrist-mounteddevice, as shown in FIGS. 2A, 2B, 3A-3C, 4A, 5, and 6. The wrist-mounteddevice may be mounted to the wrist of a living subject with a wristbandor cuff, similar to a watch or bracelet. As shown in FIGS. 2A and 2B,the wrist mounted device 200 may include a mount 210 in the form of awristband 220, a measurement platform 230 positioned on the anteriorside 240 of the wearer's wrist, and a user interface 250 positioned onthe posterior side 260 of the wearer's wrist. The wearer of the devicemay receive, via the user interface 250, one or more recommendations oralerts generated either from a remote server or other remote computingdevice, or alerts from the measurement platform. Such a configurationmay be perceived as natural for the wearer of the device in that it iscommon for the posterior side 260 of the wrist to be observed, such asthe act of checking a wrist-watch. Accordingly, the wearer may easilyview a display 270 on the user interface. Further, the measurementplatform 230 may be located on the anterior side 240 of the wearer'swrist where the subsurface vasculature may be readily observable.However, other configurations are contemplated.

The display 270 may be configured to display a visual indication of thealert or recommendation and/or an indication of the measuredphysiological parameters, for instance, the concentrations of certainblood analytes being measured. Further, the user interface 250 mayinclude one or more buttons 280 for accepting inputs from the wearer.For example, the buttons 280 may be configured to change the text orother information visible on the display 270. As shown in FIG. 2B,measurement platform 230 may also include one or more buttons 290 foraccepting inputs from the wearer. The buttons 290 may be configured toaccept inputs for controlling aspects of the data collection system,such as initiating a measurement period, or inputs indicating thewearer's current health state (i.e., normal, migraine, shortness ofbreath, heart attack, fever, “flu-like” symptoms, food poisoning, etc.).

In another example wrist-mounted device 300, shown in FIGS. 3A-3C, themeasurement platform 310 and user interface 320 are both provided on thesame side of the wearer's wrist, in particular, the anterior side 330 ofthe wrist. On the posterior side 340, a watch face 350 may be disposedon the strap 360. While an analog watch is depicted in FIG. 3B, one ofordinary skill in the art will recognize that any type of clock may beprovided, such as a digital clock.

As can be seen in FIG. 3C, the inner face 370 of the measurementplatform 310 is intended to be worn proximate to the wearer's body. Adata collection system 380 housed on the measurement platform 310 mayinclude a detector 382, a signal source 384 and a collection magnet 386.As described above, the signal source 384 and the collection magnet 386may not be provided in all embodiments of the wearable device.

In a further example shown in FIGS. 4A and 4B, a wrist mounted device400 includes a measurement platform 410, which includes a datacollection system 420, disposed on a strap 430. Inner face 440 ofmeasurement platform may be positioned proximate to a body surface sothat data collection system 420 may interrogate the subsurfacevasculature of the wearer's wrist. A user interface 450 with a display460 may be positioned facing outward from the measurement platform 410.As described above in connection with other embodiments, user interface450 may be configured to display data collected from the data collectionsystem 420, including the concentration of one or more measuredanalytes, and one or more alerts generated by a remote server or otherremote computing device, or a processor located on the measurementplatform. The user interface 420 may also be configured to display thetime of day, date, or other information that may be relevant to thewearer.

As shown in FIG. 5, in a further embodiment, wrist-mounted device 500may be provided on a cuff 510. Similar to the previously discussedembodiments, device 500 includes a measurement platform 520 and a userinterface 530, which may include a display 540 and one or more buttons550. The display 540 may further be a touch-screen display configured toaccept one or more input by the wearer. For example, as shown in FIG. 6,display 610 may be a touch-screen configured to display one or morevirtual buttons 620 for accepting one or more inputs for controllingcertain functions or aspects of the device 600, or inputs of informationby the user, such as current health state.

FIG. 7 is a simplified schematic of a system including one or morewearable devices 700. The one or more wearable devices 710 may beconfigured to transmit data via a communication interface 720 over oneor more communication networks 730 to a remote server 740. In oneembodiment, the communication interface 720 includes a wirelesstransceiver for sending and receiving communications to and from theserver 740. In further embodiments, the communication interface 720 mayinclude any means for the transfer of data, including both wired andwireless communications. For example, the communication interface mayinclude a universal serial bus (USB) interface or a secure digital (SD)card interface. Communication networks 730 may be any one of may be oneof: a plain old telephone service (POTS) network, a cellular network, afiber network and a data network. The server 740 may include any type ofremote computing device or remote cloud computing network. Further,communication network 730 may include one or more intermediaries,including, for example wherein the wearable device 710 transmits data toa mobile phone or other personal computing device, which in turntransmits the data to the server 740.

In addition to receiving communications from the wearable device 710,such as collected physiological parameter data and data regarding healthstate as input by the user, the server may also be configured to gatherand/or receive either from the wearable device 710 or from some othersource, information regarding a wearer's overall medical history,environmental factors and geographical data. For example, a user accountmay be established on the server for every wearer that contains thewearer's medical history. Moreover, in some examples, the server 740 maybe configured to regularly receive information from sources ofenvironmental data, such as viral illness or food poisoning outbreakdata from the Centers for Disease Control (CDC) and weather, pollutionand allergen data from the National Weather Service. Further, the servermay be configured to receive data regarding a wearer's health state froma hospital or physician. Such information may be used in the server'sdecision-making process, such as recognizing correlations and ingenerating clinical protocols.

Additionally, the server may be configured to gather and/or receive thedate, time of day and geographical location of each wearer of the deviceduring each measurement period. Such information may be used to detectand monitor spatial and temporal spreading of diseases. As such, thewearable device may be configured to determine and/or provide anindication of its own location. For example, a wearable device mayinclude a GPS system so that it can include GPS location information(e.g., GPS coordinates) in a communication to the server. As anotherexample, a wearable device may use a technique that involvestriangulation (e.g., between base stations in a cellular network) todetermine its location. Other location-determination techniques are alsopossible.

The server may also be configured to make determinations regarding theefficacy of a drug or other treatment based on information regarding thedrugs or other treatments received by a wearer of the device and, atleast in part, the physiological parameter data and the indicated healthstate of the user. From this information, the server may be configuredto derive an indication of the effectiveness of the drug or treatment.For example, if a drug is intended to treat nausea and the wearer of thedevice does not indicate that he or she is experiencing nausea afterbeginning a course of treatment with the drug, the server may beconfigured to derive an indication that the drug is effective for thatwearer. In another example, a wearable device may be configured tomeasure blood glucose. If a wearer is prescribed a drug intended totreat diabetes, but the server receives data from the wearable deviceindicating that the wearer's blood glucose has been increasing over acertain number of measurement periods, the server may be configured toderive an indication that the drug is not effective for its intendedpurpose for this wearer.

Further, some embodiments of the system may include privacy controlswhich may be automatically implemented or controlled by the wearer ofthe device. For example, where a wearer's collected physiologicalparameter data and health state data are uploaded to a cloud computingnetwork for trend analysis by a clinician, the data may be treated inone or more ways before it is stored or used, so that personallyidentifiable information is removed. For example, a user's identity maybe treated so that no personally identifiable information can bedetermined for the user, or a user's geographic location may begeneralized where location information is obtained (such as to a city,ZIP code, or state level), so that a particular location of a usercannot be determined.

Additionally or alternatively, wearers of a device may be provided withan opportunity to control whether or how the device collects informationabout the wearer (e.g., information about a user's medical history,social actions or activities, profession, a user's preferences, or auser's current location), or to control how such information may beused. Thus, the wearer may have control over how information iscollected about him or her and used by a clinician or physician or otheruser of the data. For example, a wearer may elect that data, such ashealth state and physiological parameters, collected from his or herdevice may only be used for generating an individual baseline andrecommendations in response to collection and comparison of his or herown data and may not be used in generating a population baseline or foruse in population correlation studies.

III. ILLUSTRATIVE ELECTRONICS PLATFORM FOR A WEARABLE DEVICE

FIG. 8 is a simplified block diagram illustrating the components of awearable device 800, according to an example embodiment. Wearable device800 may take the form of or be similar to one of the wrist-mounteddevices 200, 300, 400, 500, 600, shown in FIGS. 2A, 2B, 3A-3C, 4A, 5,and 6. However, wearable device 800 may also take other forms, such asan ankle, waist, or chest-mounted device. Alternatively, wearable device800 may be positioned on various parts of a wearer's body using, forinstance, an adhesive.

FIG. 8 shows an example of a wearable device 800 having a datacollection system 810, a user interface 820, communication platform 830for transmitting data to a server, and processor(s) 840. The componentsof the wearable device 800 may be disposed on a mount 850 for mountingthe device to an external body surface where a portion of subsurfacevasculature is readily observable.

Processor 840 may be a general-purpose processor or a special purposeprocessor (e.g., digital signal processors, application-specificintegrated circuits, etc.). The one or more processors 840 may beconfigured to execute computer-readable program instructions 870 thatare stored in the computer readable medium 860 and are executable toprovide the functionality of a wearable device 800 described herein.

The computer readable medium 860 may include or take the form of one ormore non-transitory, computer-readable storage media that may be read oraccessed by at least one processor 840. The one or morecomputer-readable storage media may include volatile and/or non-volatilestorage components, such as optical, magnetic, organic or other memoryor disc storage, which may be integrated in whole or in part with atleast one of the one or more processors 840. In some embodiments, thecomputer readable medium 860 may be implemented using a single physicaldevice (e.g., one optical, magnetic, organic or other memory or discstorage unit), while in other embodiments, the computer readable medium860 may be implemented using two or more physical devices.

Data collection system 810 includes a detector 812 and, in someembodiments, a signal source 814. As described above, detector 812 mayinclude one or more detectors configured to detect at least onephysiological parameter, which may include parameters that may relate tothe health of the person wearing the wearable device 800. For example,the detector 812 may be configured to measure blood pressure, pulserate, skin temperature, etc. Detector 812 may be configured tonon-invasively measure one or more analytes in blood circulating insubsurface vasculature proximate to the wearable device. In someexamples, detector 812 may include one or more of an optical (e.g.,CMOS, CCD, photodiode), acoustic (e.g., piezoelectric, piezoceramic),electrochemical (voltage, impedance), thermal, mechanical (e.g.,pressure, strain), magnetic, or electromagnetic (e.g., magneticresonance) sensor.

In some examples, the data collection system 810 further includes asignal source 814 for transmitting an interrogating signal that canpenetrate the wearer's skin into the portion of subsurface vasculature.In general, signal source 814 may generate an interrogation signal thatmay, in turn, for example through interactions with a target analyte,produce a response signal that may be detected by one or more of thedetectors 812. The interrogating signal can be any kind of signal thatis benign to the wearer, such as electromagnetic, magnetic, optic,acoustic, thermal, mechanical, and results in a response signal that canbe used to measure a physiological parameter or, more particularly, thatcan detect the binding of the clinically-relevant analyte to thefunctionalized particles. In one example, the interrogating signal is anelectromagnetic pulse (e.g., a radio frequency (RF) pulse) and theresponse signal is a magnetic resonance signal, such as nuclear magneticresonance (NMR). In another example, the interrogating signal is atime-varying magnetic field, and the response signal is anexternally-detectable physical motion due to the time-varying magneticfield. The time-varying magnetic field modulates the particles byphysical motion in a manner different from the background, making themeasier to detect. In a further example, the interrogating signal is anelectromagnetic radiation signal. In particular, the interrogatingsignal may be electromagnetic radiation having a wavelength betweenabout 400 nanometers and about 1600 nanometers. The interrogating signalmay, more particularly, comprise electromagnetic radiation having awavelength between about 500 nanometers and about 1000 nanometers. Inexamples where the functionalized particles include a fluorophore, theinterrogating signal may therefore be an electromagnetic radiationsignal with a wavelength that can excite the fluorophore and penetratethe skin or other tissue and subsurface vasculature (e.g., a wavelengthin the range of about 500 to about 1000 nanometers), and the responsesignal is fluorescence radiation from the fluorophore that can penetratethe subsurface vasculature and tissue to reach the detector.

The program instructions 870 stored on the computer readable medium 860may include instructions to perform or facilitate some or all of thedevice functionality described herein. For instance, in the illustratedembodiment, program instructions 870 include a controller module 872,calculation and decision module 874 and an alert module 876.

The controller module 872 can include instructions for operating thedata collection system 810, for example, the detector 812 and signalsource 814. For example, the controller 872 may activate signal source814 and/or detector 812 during one or more pre-set measurement periods.In particular, the controller module 872 can include instructions forcontrolling the signal source 814 to transmit an interrogating signal atpreset measurement times and controlling the detector 812 to receivedata representative of response signals transmitted from the portion ofsubsurface vasculature in response to the interrogating signalstransmitted at the preset measurement times.

The controller module 872 can also include instructions for operating auser interface 820. For example, controller module 872 may includeinstructions for displaying data collected by the data collection system810 and analyzed by the calculation and decision module 874, or fordisplaying one or more alerts generated by the alert module 875.Further, controller module 872 may include instructions to executecertain functions based on inputs accepted by the user interface 820,such as inputs accepted by one or more buttons disposed on the userinterface.

Communication platform 830 may also be operated by instructions withinthe controller module 872, such as instructions for sending and/orreceiving information via a wireless antenna, which may be disposed onor in the wearable device 800. The communication interface 830 canoptionally include one or more oscillators, mixers, frequency injectors,etc. to modulate and/or demodulate information on a carrier frequency tobe transmitted and/or received by the antenna. In some examples, thewearable device 800 is configured to indicate an output from theprocessor by modulating an impedance of the antenna in a manner that isperceivable by a remote server or other remote computing device.

Calculation and decision module 872 may include instructions forreceiving data from the data collection system 810 in the form of aresponsive signal, analyzing the data to determine if the target analyteis present or absent, quantify the measured physiological parameter(s),such as concentration of a target analyte, and analyzing the data todetermine if a medical condition is indicated. In particular, thecalculation and decision module 872 may include instructions fordetermining, for each preset measurement time, a concentration of aclinically-relevant analyte based on the response signal detected by thedetector at that measurement time and determining, for each presetmeasurement time, whether a medical condition is indicated based on atleast the corresponding concentration of the clinically-relevantanalyte. The preset measurement times may be set to any period and, inone example, are about one hour apart.

The program instructions of the calculation and decision module 872 may,in some examples, be stored in a computer-readable medium and executedby a processor located external to the wearable device. For example, thewearable device could be configured to collect certain data regardingphysiological parameters from the wearer and then transmit the data to aremote server, which may include a mobile device, a personal computer,the cloud, or any other remote system, for further processing.

The computer readable medium 860 may further contain other data orinformation, such as medical and health history of the wearer of thedevice, that may be necessary in determining whether a medical conditionis indicated. Further, the computer readable medium 860 may contain datacorresponding to certain analyte baselines, above or below which amedical condition is indicated. The baselines may be pre-stored on thecomputer readable medium 860, may be transmitted from a remote source,such as a remote server, or may be generated by the calculation anddecision module 874 itself. The calculation and decision module 874 mayinclude instructions for generating individual baselines for the wearerof the device based on data collected over a certain number ofmeasurement periods. For example, the calculation and decision module874 may generate a baseline concentration of a target blood analyte foreach of a plurality of measurement periods by averaging the analyteconcentration at each of the measurement periods measured over thecourse of a few days, and store those baseline concentrations in thecomputer readable medium 860 for later comparison. Baselines may also begenerated by a remote server and transmitted to the wearable device 800via communication interface 830. The calculation and decision module 874may also, upon determining that a medical condition is indicated,generate one or more recommendations for the wearer of the device based,at least in part, on consultation of a clinical protocol. Suchrecommendations may alternatively be generated by the remote server andtransmitted to the wearable device.

In some examples, the collected physiological parameter data, baselineprofiles, health state information input by device wearers and generatedrecommendations and clinical protocols may additionally be input to acloud network and be made available for download by a wearer'sphysician. Trend and other analyses may also be performed on thecollected data, such as physiological parameter data and health stateinformation, in the cloud computing network and be made available fordownload by physicians or clinicians.

Further, physiological parameter and health state data from individualsor populations of device wearers may be used by physicians or cliniciansin monitoring efficacy of a drug or other treatment. For example,high-density, real-time data may be collected from a population ofdevice wearers who are participating in a clinical study to assess thesafety and efficacy of a developmental drug or therapy. Such data mayalso be used on an individual level to assess a particular wearer'sresponse to a drug or therapy. Based on this data, a physician orclinician may be able to tailor a drug treatment to suit an individual'sneeds.

In response to a determination by the calculation and decision module874 that a medical condition is indicated, the alert module 876 maygenerate an alert via the user interface 820. The alert may include avisual component, such as textual or graphical information displayed ona display, an auditory component (e.g., an alarm sound), and/or tactilecomponent (e.g., a vibration). The textual information may include oneor more recommendations, such as a recommendation that the wearer of thedevice contact a medical professional, seek immediate medical attention,or administer a medication.

Although wearable device 800 is shown in FIG. 8 with only one signalsource (signal source 814) and one detector (detector 812), it is to beunderstood that wearable device 800 could include a plurality of signalsources and/or a plurality of detectors. For example, wearable device800 could include first and second signal sources or first and seconddetectors, as described below in relation to FIG. 10.

FIG. 9 is a simplified block diagram illustrating the components of awearable device 900, according to an example embodiment. Wearable device900 is the same as wearable device 800 in all respects, except that thedata collection system 910 of wearable device 900 further includes acollection magnet 916. In this example, the collection magnet 916 may beused to locally collect functionalized magnetic particles present in anarea of subsurface vasculature proximate to the collection magnet 916.As described above, collection magnet 916 is configured to direct amagnetic field into a portion of subsurface vasculature sufficient tocause functionalized magnetic particles to collect in a lumen of theportion of subsurface vasculature.

Wearable device 900 includes a data collection system 910, whichincludes a detector 912, a signal source 914 (if provided) and acollection magnet 916, a user interface 920, a communication interface930, a processor 940 and a computer readable medium 960 on which programinstructions 970 are stored. All of the components of wearable device900 may be provided on a mount 950. In this example, the programinstructions 970 may include a controller module 962, a calculation anddecision module 964 and an alert module 966 which, similar to theexample set forth in FIG. 8, include instructions to perform orfacilitate some or all of the device functionality described herein.Controller module 962 further includes instructions for operatingcollection magnet 916. For example, controller module 962 may includeinstructions for activating collection magnet during a measurementperiod, for a certain amount of time.

Although wearable device 900 is shown in FIG. 9 with only one signalsource (signal source 914) and one detector (detector 912), it is to beunderstood that wearable device 900 could include a plurality of signalsources and/or a plurality of detectors. For example, wearable device900 could include first and second signal sources or first and seconddetectors, as described below in relation to FIG. 10.

IV. ILLUSTRATIVE FUNCTIONALIZED PARTICLES

In some examples, the wearable devices described above obtain at leastsome of the health-related information by detecting the binding of aclinically-relevant analyte to functionalized particles, for example,microparticles or nanoparticles. The particles can be functionalized bycovalently attaching a bioreceptor designed to selectively bind orotherwise recognize a particular clinically-relevant analyte. Forexample, particles may be functionalized with a variety of bioreceptors,including antibodies, nucleic acids (DNA, siRNA), low molecular weightligands (folic acid, thiamine, dimercaptosuccinic acid), peptides (RGD,LHRD, antigenic peptides, internalization peptides), proteins (BSA,transferrin, antibodies, lectins, cytokines, fibrinogen, thrombin),polysaccharides (hyaluronic acid, chitosan, dextran, oligosaccharides,heparin), polyunsaturated fatty acids (palmitic acid, phospholipids),plasmids. The functionalized particles can be introduced into theperson's blood stream by injection, ingestion, inhalation,transdermally, or in some other manner.

The clinically-relevant analyte could be any analyte that, when presentin or absent from the blood, or present at a particular concentration orrange of concentrations, may be indicative of a medical condition orindicative that a medical condition may be imminent. For example, theclinically-relevant analyte could be an enzyme, hormone, protein, orother molecule. In one relevant example, certain protein biomarkers areknown to be predictive of an impending arterial plaque rupture. Suchprotein biomarkers are known to be present in the blood only directlyleading up to and at the onset of an arterial plaque rupture. Plaquesthat rupture cause the formation of blood clots that can block bloodflow or break off and travel to another part of the body. In either ofthese cases, if a clot blocks a blood vessel that feeds the heart, itcauses a heart attack. If it blocks a blood vessel that feeds the brain,it causes a stroke. If blood supply to the arms or legs is reduced orblocked, it can cause difficulty walking and eventually gangrene. Thepresence of these protein biomarkers in the vasculature may be detected,and the medical condition (i.e., stroke, heart attack) prevented, byproviding particles functionalized with a bioreceptor that willselectively bind to this target analyte.

The particles may be made of biodegradable or non-biodegradablematerials. For example, the particles may be made of polystyrene.Non-biodegradable particles may be provided with a removal means toprevent harmful buildup in the body. Generally, the particles may bedesigned to have a long half-life so that they remain in the vasculatureor body fluids over several measurement periods. Depending on thelifetime of the particles, however, the user of the wearable device mayperiodically introduce new batches of functionalized particles into thevasculature or body fluids.

Bioreceptors can be used in diagnostic procedures, or even in therapy todestroy a specific target, such as antitumor therapy or targetedchemotherapy. The particles may be designed to remove from the body ordestroy the target analyte once bound to the bioreceptor. Additionalfunctional groups may be added to the particles to signal that theparticles can be removed from the body through the kidneys, for example,once bound to the target analyte.

Further, the particles may be designed to either releasably orirreversibly bind to the target analyte. For example, if it is desiredfor the particles to participate in destruction or removal of the targetanalyte from the body, as described above, the particles may be designedto irreversibly bind to the target analyte. In other examples, theparticles may be designed to release the target analyte aftermeasurement has been made, either automatically or in response to anexternal or internal stimulus.

Those of skill in the art will understand the term “particle” in itsbroadest sense and that it may take the form of any fabricated material,a molecule, cryptophan, a virus, a phage, etc. Further, a particle maybe of any shape, for example, spheres, rods, non-symmetrical shapes,etc., and may be made of a solid, liquid or gaseous material orcombinations thereof. The particles can have a diameter that is lessthan about 20 micrometers. In some embodiments, the particles have adiameter on the order of about 10 nanometers to 1 micrometer. In furtherembodiments, small particles on the order of 10-100 nanometers indiameter may be assembled to form a larger “clusters” or “assemblies onthe order of 1-10 micrometers. In this arrangement, the assemblies wouldprovide the signal strength of a larger particle, but would bedeformable, thereby preventing blockages in smaller vessels andcapillaries.

Binding of the functionalized particles to a target analyte may bedetected with or without a stimulating signal input. The term “binding”is understood in its broadest sense to include any detectableinteraction between the receptor and the target analyte. For example,some particles may be functionalized with compounds or molecules, suchas fluorophores or autofluorescent, luminescent or chemiluminescentmarkers, which generate a responsive signal when the particles bind tothe target analyte without the input of a stimulus. In other examples,the functionalized particles may produce a different responsive signalin their bound versus unbound state in response to an external stimulus,such as an electromagnetic, acoustic, optical, or mechanical energy.

Further, the particles may be formed from a paramagnetic orferromagnetic material or be functionalized with a magnetic moiety. Themagnetic properties of the particles can be exploited in magneticresonance detection schemes to enhance detection sensitivity. In anotherexample, an external magnet may be used to locally collect the particlesin an area of subsurface vasculature during a measurement period. Suchcollection may not only increase the differential velocity betweenparticles and analytes, hence surveying a much larger volume per unittime, but may also enhance the signal for subsequent detection.

V. ILLUSTRATIVE METHODS FOR REDUCING NOISE IN A WEARABLE DEVICE

FIG. 10 is a flowchart of a method 1000 for reducing the influence ofnoise when taking non-invasive, in vivo, real-time measurements ofphysiological parameters using a wearable device. Block 1010 includesproviding, in a wearable medical diagnostic device, a first and a secondoptical signal transmitted from within a lumen of subsurfacevasculature. The first optical signal includes an unfiltered targetsignal and a first noise signal and the second optical signal includes asecond noise signal. The first and second noise signals are correlatedand a quotient of the unfiltered target signal and the first noisesignal includes an unfiltered signal to noise ratio. Block 1020 includesdetermining a filtered signal, based at least on the unfiltered targetsignal, the first noise signal, and the second noise signal. Thefiltered signal includes a filtered target signal and a filtered noisesignal. A quotient of the filtered target signal and the filtered noisesignal includes a filtered signal to noise ratio wherein the filteredsignal to noise ratio is higher than the unfiltered signal to noiseratio.

In an illustrative embodiment, the wearable device may be mounted to abody surface of a human subject, wherein the body surface is proximateto a portion of subsurface vasculature. The wearable device, via asignal source, may transmit an interrogating signal into the portion ofsubsurface vasculature. In some examples, a response signal is generatedin response to the interrogating signal. For instance, functionalizedparticles may be configured to bind to the clinically-relevant analyteand may comprise a receptor, such as an antibody. The term “bind” mayalso include any detectable interaction between the clinically-relevantanalyte and the functionalized particles.

The wearable device, via at least one detector, may detect the responsesignal transmitted from the portion of subsurface vasculature, whereinthe response signal is related to binding of a clinically-relevantanalyte to functionalized particles present in a lumen of the subsurfacevasculature. Additionally or alternatively, the response signal mayinclude optical measurements based on transmission, reflection, orabsorbance of light. The response signal may be considered as the firstoptical signal and may include components based on the response signalas well as noise. In other words, the response signal may be describedas including the unfiltered target signal and the first noise signal. Insome embodiments, the response signal may include the output of the oneor more detectors.

The second optical signal may be detected via at least one detector. Thesecond optical signal includes the second noise signal, which iscorrelated to the first noise signal. Further, the second optical signalmay, but need not, include other components related to the responsesignal. The first and second noise signals may be correlated if thenoise signal components include commonly correlated noise types such as:external noise pick-up, capacitive or inductive coupling, ground loops,scanning noise, or power source noise (e.g. 60 Hz hum). Additionally oralternatively, the first and second noise signals may be correlatedbased on their variance, distribution, and spectral density. In otherwords, the first and second noise signals may be correlated if thesignals resemble one another and/or one of the noise signals may bepredicted based on the other. The first and second noise signals couldbe positively and/or negatively correlated in one or both of time andstate. Other types of correlated noise are possible and contemplatedherein.

Noise sources that may contribute to the first and second noise signalsmay include, but are not limited to, those associated with variableoptical coupling to skin or tissue, variation in optical properties ofskin or tissue over time due to changes in humidity, temperature,hydration, variations in optical properties between individuals,variations in ambient light sources into detectors, and instrument anddetector noise, which may include electrical noise, radio frequency ormagnetic interference noise, or noise caused by mechanical movement ofthe detector or its components. Noise sources may be present both withinthe wearable medical diagnostic device as well as external to thedevice.

Determining a filtered signal may include various signal processing, or“denoising”, algorithms. Generally, methods contemplated herein includetechniques that separate the target signal from noise signals. In anillustrative embodiment, subtraction of a “background” noise signal maybe performed. In other words, the second optical signal may besubtracted from the first optical signal. In another embodiment, when adetector array is utilized, demosaicing may be performed based on thecorrelation between the first and second noise signals. Alternatively oradditionally, methods herein may include denoising algorithms known inthe art such as the Bayesian Least Squares GSM, Probshrink, or Non LocalMeans (NLMS) methods. Other methods operable to separate a target signalfrom a noise signal are contemplated within the scope of thisdisclosure.

Upon determining a filtered signal, the wearable device may thendetermine the presence, absence and/or a concentration of theclinically-relevant analyte based on the response signal and whether amedical condition is indicated based on at least the presence, absenceand/or concentration of the clinically-relevant analyte. Further, inexamples where the functionalized particles are magnetic, the wearabledevice may further direct a magnetic field into the portion ofsubsurface vasculature, the magnetic field being sufficient to cause thefunctionalized magnetic particles to collect in a lumen of the portionof subsurface vasculature.

The wearable medical diagnostic device may carry out Block 1010 andBlock 1020 of method 1000 in various ways. For example, in an effort toseparate out noise from the response signal, several differentnoise-reduction measurement techniques may be utilized.

In an illustrative embodiment, the medical diagnostic device may includea first detector and a second detector and a source configured toilluminate an analyte within the lumen. The analyte, which may include afluorophore, may be configured to emit emission light at a knownwavelength and/or set of wavelengths upon illumination by the source.Thus, method 1000 may optionally include spectrally separating at leasta portion of the emission light into at least a first spectral band anda second spectral band. For example, the fluorophore may be configuredto emit within the first spectral band while the autofluorescence of theilluminated tissue may occur within the second spectral band. In such ascenario, the first optical signal (obtained by the first detector) mayinclude a portion of the first spectral band and the second opticalsignal (obtained by the second detector) may include a portion of thesecond spectral band. Spectral separation may be performed using opticalband pass filters or using a grating spectrometer. Determining thefiltered signal may include subtracting the autofluorescence signalportion from the target signal portion. Alternatively, a fluorophoreneed not be used. For example, the autofluorescence of different tissuesmay occur within different wavebands, which may then be spectrallyseparated using the above method. As a further alternative, the secondspectral band may be chosen to coincide with the emission spectrum ofthe autofluorescence. Other choices are possible for the first and thesecond spectral bands.

In another illustrative embodiment, the wearable diagnostic device mayinclude a detector and a first and a second source. The first and secondsources may be configured to illuminate the analyte within the lumen ata first and second wavelength (or waveband), respectively. In such ascenario, the method 1000 may optionally include periodicallyilluminating the analyte with the first source at a given period and agiven duty cycle. Generally, the duty cycle may be configured to be lessthan one. The method 1000 may optionally include periodicallyilluminating the analyte with the second source for at least a portionof the given period while the first source is not illuminating theanalyte. For example, the first and second sources may alternate with a50% duty cycle. The frequency may range from mHz to tens of kHz. Themethod 1000 may optionally include detecting the first optical signalwith the detector while the analyte is illuminated by the first sourceand detecting the second optical signal with the detector while theanalyte is illuminated by the second source. In some exampleembodiments, the first source may be configured to substantiallyoptically excite the analyte of interest while the second source may beconfigured to substantially not optically excite the analyte.Alternatively, the first and second sources may be configured tosubstantially optically excite the analyte to different respectivewavelengths. Further, while a simple alternating illumination techniqueis disclosed above, more complex pulse sequences, such as pulse codemodulation schemes, may be used to optimize duty cycle or to improve theseparation of noise from the signal of interest.

In yet another illustrative embodiment, the wearable diagnostic devicemay include a detector and a source. In such a scenario, a primarycontrast agent and a normalization contrast agent may be introduced intothe lumen. The primary contrast agent may be configured to fluoresce ata first spectral maximum and the normalization contrast agent may beconfigured to fluoresce at a second spectral maximum. In such anembodiment, the method 1000 may optionally include illuminating thelumen with the source, detecting the first optical signal substantiallyat the first spectral maximum, and detecting the second optical signalsubstantially at the second spectral maximum. A spectrometer may be usedto obtain the spectral information about the emission signal in responseto the source illumination. Additionally or alternatively, thenormalization contrast agent may be configured to provide a calibrationreference for an optical coupling factor between the detector and theskin surface. For example, a “baseline spectra” may be obtained afterthe normalization contrast agent is introduced into the lumen, butbefore the primary contrast introduced into same. The normalizationcontrast agent may be introduced into circulation and/or mayalternatively be introduced into the skin as a “tattoo” such that it issubstantially immobile under the detection area. A further marker orprobe utilizing the normalization contrast agent may be introduced toserve as a calibration guide for techniques that involve, for instance,adaptive optics or spatially modulated light.

In a further illustrative embodiment, the lumen may include a first anda second portion and the wearable medical diagnostic device may includea source configured to illuminate at least the first and second portionsat a spectral illumination maximum. In such a scenario, the method 1000may optionally include illuminating the first and second portions of thelumen with the source so as to cause a first portion emission and asecond portion emission. The method 1000 may also include detecting thefirst optical signal from the first portion emission (e.g., with a firstdetector) and detecting the second optical signal from the secondportion emission (e.g., with a second detector). In other words, two ormore spatially separated detectors may obtain optical signals fromvarious locations along the lumen. The two or more spatially separateddetectors may include an array of photodiodes or a multi-elementdetector. Accordingly, noise may be separated from the response signalwhen the noise signal contributions from the various locations arecorrelated. Optionally, such a scenario need only include one detectorconfigured to detect the first portion emission as distinct from thesecond portion emission. That is, the detector may be moved to beproximate to the first and second portions of the lumen or light fromthe respective portions of the lumen may otherwise be distinctlytransmitted to the detector.

In another illustrative embodiment, the wearable medical diagnosticdevice may include a detector wherein illuminating the first and secondportions of the lumen includes illuminating the first and secondportions of the lumen at a first time and a second time, respectively.In such a scenario, the method 1000 may include the detector detectingthe first optical signal during the first time and may additionallyinclude the detector detecting the second optical signal during thesecond time. Put another way, various elements of method 1000 may becarried out at different times so as to determine a filtered signal.

In yet another illustrative embodiment, the wearable medical diagnosticdevice may include a detector and a source. The method 1000 may alsoinclude illuminating the lumen with the source, modulating the firstand/or second noise signals, and then detecting the first and secondoptical signals with the detector. Modulating the first and second noisesignals may include modulating the source illumination in a way thatneed not substantially change the emission of the analyte of interest.For example, the source illumination may increase in intensity at awavelength or waveband different from a waveband that may induceemission from an analyte such as a fluorophore. In so doing, theemission of background tissues, for instance, may be modulated. Signalprocessing may be used to subtract or otherwise separate the noisesignals from the signal of interest. Alternatively or additionally,non-optical methods could be used to modulate the background noisesignal. For example, changing the temperature of the surrounding tissuesmay affect emission, absorption, and/or reflective properties of saidtissues. In such a scenario, the first and second noise signals may beaffected or modulated substantially independent of the signal ofinterest. In another example, acoustic modulation of surrounding tissuesmay change the emission, absorption, and/or reflective properties of thetissues. Again, the acoustic modulation of surrounding tissues mayaffect the first and second noise signals substantially independent ofthe signal of interest. Other ways of modulating the background noisesignals will be evident to those with skill in the art and may includeother optical and non-optical means for changing the background noisesignal substantially independent from the signal of interest.

The method 1000 may include other ways of performing gradiometricmeasurements. For example, any combination of emission unmixing orexcitation unmixing may be included in the method 1000. Furthermore, anycombination of methods known in the art to provide backgroundnormalization and/or background modulation may be included in the method1000.

VI. ILLUSTRATIVE WEARABLE MEDICAL DIAGNOSTIC SYSTEM WITH NOISE REDUCTION

FIGS. 11A-11B, 12A-12B, and 13A-13B are partial cross-sectional sideviews of a human wrist illustrating the operation of various examples ofa wrist-mounted device. In the example shown in FIGS. 11A and 11B, thewrist-mounted device 1100 includes a measurement platform 1110 mountedon a strap or wrist-band 1120 and oriented on the anterior side 1190 ofthe wearer's wrist. Measurement platform 1110 is positioned over aportion of the wrist where subsurface vasculature 1130 is easilyobservable. Functionalized particles 1140 have been introduced into alumen of the subsurface vasculature by one of the means discussed above.In this example, measurement platform 1110 includes a data collectionsystem having both a detector 1150 and a signal source 1160. FIG. 11Aillustrates the state of the subsurface vasculature when measurementdevice 1100 is inactive. The state of the subsurface vasculature duringa measurement period is illustrated in FIG. 11B. At this time, signalsource 1160 is transmitting an interrogating signal 1162 into theportion of subsurface vasculature and detector 1150 is receiving aresponse signal 1152 generated in response to the interrogating signal1162. The response signal 1152 is related to the binding of aclinically-relevant analyte present in the subsurface vasculature to thefunctionalized particles 1140. As described above, in some embodiments,an interrogating signal may not be necessary to generate a responsesignal related to the binding of an analyte to the functionalizedparticles.

Similar to the system depicted in FIGS. 11A and 11B, FIGS. 12A and 12Billustrate a wrist-mounted device 1200 including a measurement platform1210 mounted on a strap or wristband 1220 and oriented on the anteriorside 1290 of the wearer's wrist. In this example, measurement platform1210 includes a data collection system having a detector 1250, a signalsource 1260 and a collection magnet 1270. FIG. 12A illustrates the stateof the subsurface vasculature when measurement device 1200 is inactive.The state of the subsurface vasculature when measurement device 1200 isactive during a measurement period is illustrated in FIG. 12B. At thistime, collection magnet 1270 generates a magnetic field 1272 sufficientto cause functionalized magnetic particles 1240 present in a lumen ofthe subsurface vasculature 1230 to collection in a region proximal tothe magnet 1270. Signal source 1260 transmits an interrogating signal1262 into the portion of subsurface vasculature and detector 1250 isreceiving a response signal 1252 generated in response to theinterrogating signal 1262. The response signal 1252 is related to thebinding of a clinically relevant analyte present in the subsurfacevasculature to the functionalized magnetic particles 1240. As describedabove, in some embodiments, an interrogating signal may not be necessaryto generate a response signal related to the binding of an analyte tothe functionalized magnetic particles.

FIGS. 13A and 13B illustrate a further embodiment of a wrist-mounteddevice 1300 having a measurement platform 1310 disposed on a strap 1320,wherein the detector 1350 and signal source 1360 are positioned on theposterior side 1390 of the wearer's wrist and the collection magnet 1370is disposed on the anterior side 1380 of the wearer's wrist. Similar tothe embodiments discussed above, FIG. 13A illustrates the state of thesubsurface vasculature when measurement device 1300 is inactive. Thestate of the subsurface vasculature when measurement device 1300 isactive during a measurement period is illustrated in FIG. 13B. At thistime, collection magnet 1370 generates a magnetic field 1232 sufficientto cause functionalized magnetic particles 1340 present in a lumen ofthe subsurface vasculature 1330 to collection in a region proximal tothe magnet 1370. Signal source 1360 transmits an interrogating signal1362 into the portion of subsurface vasculature and detector 1350 isreceiving a response signal 1352 generated in response to theinterrogating signal 1262. The response signal 1352 is related to thebinding of a clinically relevant analyte present in the subsurfacevasculature to the functionalized magnetic particles 1340. As describedabove, in some embodiments, an interrogating signal may not be necessaryto generate a response signal related to the binding of an analyte tothe functionalized magnetic particles.

Both FIGS. 12B and 13B illustrate the path of the interrogating signal(1262, 1362) transmitted by the signal source (1260, 1360) and theresponsive signal (1252, 1352) detected by the detector (1250, 1350)essentially overlapping over a portion of subsurface vasculature. Insome examples, the signal source (1260, 1360) and the detector (1250,1350) may be angled towards each other so that they are interrogatingand detecting from essentially the same area of subsurface vasculature.However, in some instances, such as in the example shown in FIG. 11B,the paths of the interrogating signal (1262, 1362) transmitted by thesignal source (1260, 1360) and the responsive signal (1252, 1352)detected by the detector (1250, 1350) may not overlap.

The signal-to-noise ratio (SNR) in an analyte detection system, such asany of those described above, may be increased by modulating the analyteresponse signal transmitted from the subsurface vasculature (or otherbody system) with respect to the background signal and, in some cases,an unbound particle response signal. Such modulation can increase thesystem's sensitivity and ability to discern between target analytespresent in the blood or other bodily fluids, versus other analytes,particles, cells, molecules, blood components, bone and tissues, etc.This can be particularly valuable with some methods of analytecharacterization, such as optical methods, or where the target analytesare rare in the blood or are of a relatively small size and withfluorescence detection techniques, which can often suffer from lowresolution because other tissues, cells, and molecules in the body mayhave some inherent fluorescent properties, creating a high level ofbackground noise.

FIG. 14 is a functional block diagram of a wearable medical diagnosticsystem with noise reduction 1400, according to an illustrativeembodiment. The wearable medical diagnostic system 1400 may include asource 1402, filters 1410 and 1412, a dichroic beamsplitter 1404, lenses1406 and 1408, a target location 1420, and a detector 1450. The source1402 may be configured to transmit an interrogating signal 1430 via thedichroic beamsplitter 1404, and lens 1408 towards the target location1420. The dichroic beamsplitter 1404 may be configured to reflect and/ortransmit light based, at least in part, on the wavelength of such light.For example, the dichroic beamsplitter 1404 may be configured to reflectthe interrogating signal 1430, which may include light at firstwavelength and/or a first waveband, from source 1402 towards the targetlocation 1420.

The source 1402 may include a laser, a light-emitting diode (LED), oranother device configured to produce light. The source 1402 may beconfigured to produce light at or around a particular wavelength orwithin a particular waveband. For example, the source 1402 may beconfigured to emit light at a wavelength known to cause a givenfluorophore to emit light at a second wavelength or second waveband. Thelight from source 1402 may be substantially collimated, such as from alaser. Alternatively, the light from source 1402 may be collected andcollimated and/or focused so as to illuminate target location 1420. Thesource 1402 may be configured to provide continuous illumination.Alternatively, source 1402 may provide pulsed or otherwise intermittentlight. In an illustrative embodiment source 1402 may include a LED thatprovides light substantially in the infrared spectral band. Source 1402may additionally be configured to provide illumination at more than onewavelength or over more than one waveband. Yet further, source 1402 mayrepresent more than one light source. For example, source 1402 may be anarray of light emitters or may include at least two light sources atspatially-separated locations. In other words, although FIG. 14 depictsone source 1402 and one associated optical path (e.g. illustrated byinterrogation signal 1430), multiple sources and/or multiple opticalpaths could be utilized within the scope of the present disclosure.

In one example, multiple sources 1402 may be configured to spatiallymodulate the analyte response signal. For example, a spatial modulationmay exploit the speed, rotation, size, thermodynamic properties,hydrodynamic properties, etc. of the bound particles, versus unboundparticles and other items that are not of interest, travelling near thetarget location 1440 to distinguish the analyte response signal. Forexample, an analyte-bound particle is going to have a different size andshape than an unbound particle and, therefore, may travel through thesubsurface vasculature a different speed, thereby modulating betweenbound and unbound particles. In one example, analyte-bound magneticparticles may travel through the subsurface vasculature at a differentspeed when subject to a magnetic field than unbound magnetic particles.The multiple sources 1402 may be used to exploit this difference inspeed to differentiate the analyte response signal from other signalstransmitted from the body.

In an illustrative embodiment, a first source and a second source may beconfigured to illuminate the target location 1420, which may include thelocation of a target analyte. The first source may be configured toprovide light substantially at a first wavelength and the second sourcemay be configured to provide light substantially at a second wavelength.Furthermore, the first source may periodically illuminate the targetlocation 1420 at a given period and a given duty cycle. The secondsource may periodically illuminate the target location 1420 while thefirst source is not illuminating the target location 1420. In such ascenario, the detector 1450 may detect the unfiltered target signal andthe first noise signal while the target location 1420 is illuminated bythe first source. Additionally, the detector 1450 may detect the secondnoise signal while the target location 1420 is illuminated by the secondsource.

The target location 1420 may include a lumen of the subsurfacevasculature as described herein, for example with reference to FIGS.11A&B. The target location 1420 may alternatively or additionallyinclude other locations or structures, such as a skin surface, a bone, ablood vessel, a muscle, and/or another part of a body. The targetlocation 1420 may alternatively represent blood, another bodily fluid,or another medium in which analytes of interest may be detected.

When light is emitted or reflected from the target location 1420, aresponse signal 1440 may be collected by the wearable medical diagnosticsystem 1400. In an illustrative embodiment, the response signal 1440 maybe collected with lens 1408. The dichroic beamsplitter 1404 may beconfigured to substantially transmit the response signal 1440, which mayinclude a second wavelength and/or a second waveband. In such ascenario, the emitted light may pass substantially through the dichroicbeamsplitter 1404 towards the detector 1450. Specifically, the responsesignal 1440 may pass through emission filter 1410 and may be focused bylens 1406 onto the detector 1450.

Detector 1450 may be configured to sense light at various wavelengths orwithin various wavebands. For example, detector 1450 may be configuredto sense infrared light, visible light, ultraviolet light, and/or anyother wavelength or waveband of light.

Filters 1410 and 1412 may be spectral filters configured to block,attenuate, and/or transmit various wavelengths and/or wavebands oflight. The filters could be, for example, gratings or prisms. Othertypes of filters are possible as well.

Although lens 1408 is depicted as focusing the interrogating signal 1430onto the target location 1420, lens 1408 may affect the interrogatingsignal 1430 in other ways. For example, lens 1408 may represent acollimating lens. In such a scenario, the collimating lens may be usedso as to direct a collimated optical beam towards the target location1420. Alternatively or additionally, the lens 1408 may represent aspatial light modulator. In such a scenario, the spatial light modulatormay be utilized to direct light towards various spatial locations nearthe target location 1420. Alternatively, the spatial light modulator maybe used to modulate or block various portions of the interrogatingsignal 1430 and/or modulate or block the entire interrogating signal1430. Furthermore, lens 1408 may represent more than one optical lens.For example, instead of using lens 1408 as a focusing and collectionoptic, two or more lenses could be utilized to achieve one or more offocusing the interrogating signal 1430 and collecting the responsesignal 1440. Other optical elements or combinations thereof may be usedin place of lens 1408.

Similarly, other optical elements or combinations thereof may be used inplace of lens 1406. For example, lens 1406 may represent a spatial lightmodulator, a collimating lens, a focusing mirror, a plane mirror, oranother optical element.

Dichroic beamsplitter 1404 may represent various optical componentsconfigured to reflect and/or transmit light based, in part, on thewavelength of the incoming light. In an illustrative embodiment, thedichroic beamsplitter may include a surface 1403 configured to reflectand/or transmit light based on its wavelength. Alternatively, dichroicbeamsplitter 1404 may represent a prism or a grating, such as those usedin a grating spectrometer.

FIG. 15 is a functional block diagram of a wearable medical diagnosticsystem with noise reduction 1500, according to an illustrativeembodiment. Wearable medical diagnostic system 1500 may include a source1502, filters 1510, 1512, and 1514, lenses 1506, 1508, and 1516,detectors 1550 and 1552, as well as dichroic beamsplitters 1504 and1505. In an illustrative embodiment, interrogating signal 1530 may beemitted from source 1502. The interrogating signal 1530 may be directedtowards a target location 1520 via dichroic beamsplitter 1504 and 1508.The interrogating signal may interact with analytes near the targetlocation 1520. The analytes and/or bound particles may emit light thatmay be collected as a response signal 1540. The response signal 1540 maybe directed towards dichroic beamsplitter 1505 via lens 1508 anddichroic beamsplitter 1504. Dichroic beamsplitter 1505 may reflectand/or transmit a portion of the response signal 1540 towards detector1550 or detector 1552. For example, dichroic beamsplitter 1505 may beconfigured to reflect a first portion of response signal 1560 towardsdetector 1552 based, at least in part, on the wavelength or waveband ofthe first portion of response signal 1560. Additionally oralternatively, dichroic beamsplitter 1552 may be configured to transmita second portion of response signal 1570 towards detector 1550 based, atleast in part, on the wavelength or waveband of the second portion ofresponse signal 1570.

In another illustrative embodiment, dichroic beamsplitter 1552 mayrepresent a flip mirror or another optical element configured to steeror direct at least a portion of the response signal 1540 towardsdetector 1550 and/or detector 1552. Similar to system 1400, the opticalcomponents depicted in system 1500 may be substituted with one or moreother known optical components.

One with skill in the art will recognize that various configurations ofthe wearable medical diagnostic systems 1400 and 1500 are contemplatedwithin the scope of this disclosure. The depicted configurations are notmeant to limit the numerous different optical configurations that may beused to carry out the methods disclosed herein.

The wearable medical diagnostic devices 1400 and 1500 may additionallyinclude a computing device (not shown) configured to determine afiltered signal, based at least on the response signal 1440 and 1540,which may include an unfiltered target signal, a first noise signal, anda second noise signal. The first and second noise signals may becorrelated and a quotient of the unfiltered target signal and the firstnoise signal may include an unfiltered signal to noise ratio. Thefiltered signal may include a filtered target signal and a filterednoise signal. The computing device may be configured to provide aquotient of the filtered signal and the filtered noise signal. Thequotient of the filtered signal and the filtered noise signal mayrepresent a filtered signal to noise ratio. The filtered signal to noiseratio may be higher than an unfiltered signal to noise ratio. Inreference to FIG. 10, the wearable medical diagnostic devices 1400 and1500 may be configured so as to carry out method 1000 and each of theillustrative embodiments disclosed herein.

The first and second signal may include any signal transmitted fromsomething other than what the systems 1400 and 1500 are monitoring,i.e., the target analyte(s). In some examples, the background signal maybe generated by other molecules, cells, or particles in the blood orother bodily fluids; tissue, such as skin, veins, muscle, etc.; bone; orother objects present in the wearer's body. A background signal may begenerated by excitation of these objects from the interrogating signal,such as by generating an autofluorescence signal, or due to someinherent property of these objects, such as, chemiluminescence, etc.

In an illustrative embodiment, the computing device may be configured tospectrally separate emission light (e.g. response signal 1540) into afirst spectral band and a second spectral band. For example, a firstdetector (e.g. detector 1550) may be configured to detect light withinthe first spectral band. In such a scenario, a second detector (e.g.detector 1552) may be configured to detect light within the secondspectral band.

In another illustrative embodiment, a lumen may include a primarycontrast agent configured to fluoresce at a first spectral maximum. Thelumen may additionally include a normalization contrast agent configuredto fluoresce at a second spectral maximum. In such a scenario, thecomputing device may be further configured to receive, via the detector,the unfiltered target signal and the first noise signal at the firstspectral maximum. Additionally, the computing device may be furtherconfigured to receive, via the detector, the second noise signal at thesecond spectral maximum.

In yet another illustrative embodiment, the system may be configured toilluminate a first portion and a second portion of the lumen (e.g.designating and illuminating multiple target locations 1540). In such ascenario, illumination may produce first portion emission and secondportion emission. Thus, the detector may detect the unfiltered targetsignal and the first noise signal from the first portion emission. Thedetector may also detect the second noise signal from the second portionemission.

VII. ILLUSTRATIVE NON-TRANSITIVE COMPUTER READABLE MEDIUM

Some or all of the functions described above and illustrated in FIG. 10may be performed by a computing device in response to the execution ofinstructions stored in a non-transitory computer readable medium. Thenon-transitory computer readable medium may be, for example, a randomaccess memory (RAM), a read-only memory (ROM), a flash memory, a cachememory, one or more magnetically encoded discs, one or more opticallyencoded discs, or any other form of non-transitory data storage. Thenon-transitory computer readable medium may also be distributed amongmultiple data storage elements, which may be remotely located from eachother. The computing device that executes the stored instructions mayinclude the processor 940 as described and illustrated in FIG. 9.Additionally or alternatively, the computing device may include anothercomputing device, such as a server in a server network.

The non-transitory computer readable medium may store instructionsexecutable by a computing device (e.g. processor 940 as described inreference to FIG. 9) to cause the computing device to perform any of thefunctions described herein.

In one example, the functions include receiving, in a wearable medicaldiagnostic device, a first and a second optical signal transmitted fromwithin a lumen of subsurface vasculature. The first optical signalincludes an unfiltered target signal and a first noise signal. Thesecond optical signal includes a second noise signal. The first andsecond noise signals are correlated. The quotient of the unfilteredtarget signal and the first noise signal includes an unfiltered signalto noise ratio. The functions further include determining a filteredsignal, based at least on the unfiltered target signal, the first noisesignal, and the second noise signal. The filtered signal includes afiltered target signal and a filtered noise signal. A quotient of thefiltered target signal and the filtered noise signal includes a filteredsignal to noise ratio in which the filtered signal to noise ratio ishigher than the unfiltered signal to noise ratio.

VIII. CONCLUSION

Where example embodiments involve information related to a person or adevice of a person, some embodiments may include privacy controls. Suchprivacy controls may include, at least, anonymization of deviceidentifiers, transparency and user controls, including functionalitythat would enable users to modify or delete information relating to theuser's use of a product.

Further, in situations where embodiments discussed herein collectpersonal information about users, or may make use of personalinformation, the users may be provided with an opportunity to controlwhether programs or features collect user information (e.g., informationabout a user's medical history, social network, social actions oractivities, profession, a user's preferences, or a user's currentlocation), or to control whether and/or how to receive content from thecontent server that may be more relevant to the user. In addition,certain data may be treated in one or more ways before it is stored orused, so that personally identifiable information is removed. Forexample, a user's identity may be treated so that no personallyidentifiable information can be determined for the user, or a user'sgeographic location may be generalized where location information isobtained (such as to a city, ZIP code, or state level), so that aparticular location of a user cannot be determined. Thus, the user mayhave control over how information is collected about the user and usedby a content server.

The particular arrangements shown in the Figures should not be viewed aslimiting. It should be understood that other embodiments may includemore or less of each element shown in a given Figure. Further, some ofthe illustrated elements may be combined or omitted. Yet further, anillustrative embodiment may include elements that are not illustrated inthe Figures.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopebeing indicated by the following claims.

What is claimed is:
 1. A method comprising: providing, in a wearablemedical diagnostic device, a first and a second optical signaltransmitted from within a lumen of subsurface vasculature, wherein thefirst optical signal comprises an unfiltered target signal and a firstnoise signal and the second optical signal comprises a second noisesignal, wherein the first and second noise signals are correlated andwherein a quotient of the unfiltered target signal and the first noisesignal comprises an unfiltered signal to noise ratio; and determining afiltered signal, based at least on the unfiltered target signal, thefirst noise signal, and the second noise signal, wherein the filteredsignal comprises a filtered target signal and a filtered noise signal,and wherein a quotient of the filtered target signal and the filterednoise signal comprises a filtered signal to noise ratio wherein thefiltered signal to noise ratio is higher than the unfiltered signal tonoise ratio.
 2. The method of claim 1 wherein the wearable medicaldiagnostic device comprises a detector and at least a first source and asecond source wherein the first and second sources are configured toilluminate an analyte within the lumen substantially at a firstwavelength and a second wavelength, respectively, and the method furthercomprising: periodically illuminating the analyte with the first sourceat a given period and a given duty cycle wherein the duty cycle is lessthan one; periodically illuminating the analyte with the second sourceat the given period, wherein the second source illuminates the analytefor at least a portion of the given period while the first source is notilluminating the analyte; detecting the first optical signal with thedetector while the analyte is illuminated by the first source; anddetecting the second optical signal with the detector while the analyteis illuminated by the second source.
 3. The method of claim 2 whereinthe first source is configured to substantially optically excite theanalyte and the second source is configured to substantially notoptically excite the analyte.
 4. The method of claim 1 wherein thewearable medical diagnostic device comprises a detector and a source andwherein the lumen comprises a primary contrast agent configured tofluoresce at a first spectral maximum and a normalization contrast agentconfigured to fluoresce at a second spectral maximum, the method furthercomprising: illuminating the lumen with the source; detecting the firstoptical signal substantially at the first spectral maximum; anddetecting the second optical signal substantially at the second spectralmaximum.
 5. The method of claim 4 wherein the normalization contrastagent is configured to provide a calibration reference for an opticalcoupling factor between the detector and a skin surface.
 6. The methodof claim 1 wherein the lumen comprises at least a first and a secondportion and the wearable medical diagnostic device comprises a sourceconfigured to illuminate at least the first and second portions at aspectral illumination maximum, the method further comprising:illuminating the first and second portions of the lumen with the sourceso as to cause a first portion emission and a second portion emission;detecting the first optical signal from the first portion emission; anddetecting the second optical signal from the second portion emission. 7.The method of claim 6 wherein the wearable medical diagnostic devicefurther comprises a first and a second detector configured to detect thefirst and the second optical signals, respectively.
 8. The method ofclaim 6 wherein the wearable medical diagnostic device further comprisesa detector, wherein illuminating the first and second portions of thelumen comprises illuminating the first and second portions of the lumenat a first time and a second time, respectively, and wherein detectingthe first optical signal comprises the detector detecting the firstoptical signal during the first time and wherein detecting the secondoptical signal comprises the detector detecting the second opticalsignal during the second time.
 9. A wearable medical diagnostic device,comprising: at least one detector configured to provide an unfilteredtarget signal, a first noise signal, and a second noise signal, whereinthe unfiltered target signal is transmitted substantially from within alumen of subsurface vasculature, wherein the first and second noisesignals are correlated, and wherein a quotient of the unfiltered targetsignal and the first noise signal comprises an unfiltered signal tonoise ratio; and a computing device configured to determine a filteredsignal, based at least on the unfiltered target signal, the first noisesignal, and the second noise signal, wherein the filtered signalcomprises a filtered target signal and a filtered noise signal andwherein a quotient of the filtered target signal and the filtered noisesignal comprises a filtered signal to noise ratio in which the filteredsignal to noise ratio is higher than the unfiltered signal to noiseratio.
 10. The wearable medical diagnostic device of claim 9 furthercomprising: a first source; and a second source, wherein the first andsecond sources are configured to illuminate an analyte within the lumensubstantially at a first and a second wavelength, respectively, andwherein the computing device is further configured to: periodicallyilluminate the analyte with the first source at a given period and agiven duty cycle wherein the duty cycle is less than one; periodicallyilluminate the analyte with the second source at the given period,wherein the second source illuminates the analyte for at least a portionof the given period while the first source is not illuminating theanalyte; detect the unfiltered target signal and the first noise signalwith the at least one detector while the analyte is illuminated by thefirst source; and detect the second noise signal with the at least onedetector while the analyte is illuminated by the second source.
 11. Thewearable medical diagnostic device of claim 9 further comprising: asource, wherein the lumen comprises a primary contrast agent configuredto fluoresce at a first spectral maximum and a normalization contrastagent configured to fluoresce at a second spectral maximum, and whereinthe computing device is further configured to: illuminate the lumen withthe source; detect, with the at least one detector, the unfilteredtarget signal and the first noise signal substantially at the firstspectral maximum; and detect, with the at least one detector, the secondnoise signal substantially at the second spectral maximum.
 12. Thewearable medical diagnostic device of claim 9, wherein the lumencomprises at least a first and a second portion and the wearable medicaldiagnostic device further comprises a source configured to illuminate atleast the first and second portions, and wherein the computing device isfurther configured to: illuminate the first and second portions of thelumen with the source so as to cause a first portion emission and asecond portion emission; detect, with the at least one detector, theunfiltered target signal and the first noise signal from the firstportion emission; and detect, with the at least one detector, the secondnoise signal from the second portion emission.
 13. A non-transitorycomputer readable medium having stored therein instructions executableby a computing device to cause the computing device to perform functionscomprising: receiving, in a wearable medical diagnostic device, a firstand a second optical signal transmitted from within a lumen ofsubsurface vasculature, wherein the first optical signal comprises anunfiltered target signal and a first noise signal and the second opticalsignal comprises a second noise signal, wherein the first and secondnoise signals are correlated and wherein a quotient of the unfilteredtarget signal and the first noise signal comprises an unfiltered signalto noise ratio; and determining a filtered signal, based at least on theunfiltered target signal, the first noise signal, and the second noisesignal, wherein the filtered signal comprises a filtered target signaland a filtered noise signal, and wherein a quotient of the filteredtarget signal and the filtered noise signal comprises a filtered signalto noise ratio in which the filtered signal to noise ratio is higherthan the unfiltered signal to noise ratio.
 14. The non-transitorycomputer readable medium of claim 13, wherein the wearable medicaldiagnostic device comprises a detector and at least a first source and asecond source wherein the first and second sources are configured toilluminate an analyte within the lumen substantially at a firstwavelength and a second wavelength, respectively, and the non-transitorycomputer readable medium further comprising: causing the first source toperiodically illuminate the analyte at a given period and a given dutycycle wherein the duty cycle is less than one; causing the second sourceto periodically illuminate the analyte at the given period, wherein thesecond source illuminates the analyte for at least a portion of thegiven period while the first source is not illuminating the analyte;receiving the first optical signal from the detector while the analyteis illuminated by the first source; and receiving the second opticalsignal from the detector while the analyte is illuminated by the secondsource.
 15. The non-transitory computer readable medium of claim 13,wherein the wearable medical diagnostic device comprises a detector anda source and wherein the lumen comprises a primary contrast agentconfigured to fluoresce at a first spectral maximum and a normalizationcontrast agent configured to fluoresce at a second spectral maximum, andthe non-transitory computer readable medium further comprising: causingthe lumen to be illuminated by the source; receiving the first opticalsignal substantially at the first spectral maximum; and receiving thesecond optical signal substantially at the second spectral maximum.